dataesr/scientific-paragraphs-categorization huggingface dataset:
Material and methods Patients. Data were collected from the Iranian National Obesity Surgery Database (INOSD)  12  and all surgical procedures were performed at a tertiary, academic and accredited IFSO-EC bariatric surgery center. All the patients who had undergone OAGB from September 2014 to January 2017 were evaluated. During this time, 1356 patients had undergone OAGB, including 73 cases as conversion surgery. A total of 29 patients had undergone conversional OAGB following SG due to weight regain or incomplete weight loss. We only included the 23 patients who had completed their 5-year follow up (Fig. 1 ).
Data collection. DM remission was defined as HbA1c < 6%, FBG < 100 mg/dl) in the absence of anti-diabetic medications. HTN remission was taken as being normotensive (BP < 120/80) without antihypertensive medications. Dyslipidemia remission was confined to normal lipid profile (LDL, HDL, Cholesterol, TG) without medication usage. GERD remission was defined as the absence of symptoms with no medications  14  and the GERD score was assessed using the GERD-Q questionnaire  15  in these patients. The patients with GERD score more than eight points were evaluated by EGD. DM improvement was defined as statistically significant reduction inHbA1c and FBG or decrease in antidiabetic medications requirements. HTN improvement was taken as a decrease in dosage or number of antihypertensive medications or decrease in systolic or diastolic blood pressure (BP) on the same medication.
Statistical analysis. The mean, standard deviation (SD), percentage and 95% confidence interval (CI) were reported for the description of the data. Repeated measurements were used to assess the trend of changes in weight, BMI, %TWL and %EWL after conversion surgery. Friedman's test was used for changes in the pattern of obesity associated medical problems during the time. The level of statistical significance was taken as P-value < 0. 05. All the analyses were carried out in SPSS version 25. 0 (Chicago, Illinois, USA).
Thereafter, the GdIG/Pt sample was subjected to FMR measurements. As shown in Figure  2e , the linewidth of the FMR spectra at 6 GHz for GdIG/Pt is noticeably enhanced compared to that for GdIG. The inset in Figure  2e  displays f versus H r at 375 K. The extracted ΔH as a function of H r is shown in Figure  2f  for the GdIG and GdIG/Pt films. Evidently, the slope of the linear ΔH versus f plot for the GdIG/Pt sample is larger than that for the GdIG sample. The data shown in Figure  2e ,f indicate that the Pt layer introduces additional damping (S1). The temperature dependence of the Gilbert damping (α GdIG (T)) for the GdIG film is presented in Figure  3a. The damping values were calculated to be 3. 3 × 10 -3 and 5. 8 × 10 -3 at the lowest temperature (10 K) and the highest temperature (375 K) in our experiments, respectively.
In addition, the new formulation, called the ETEM-SG, explicitly modeled the reserve capacities provided by demand response and ancillary services, such as reactive power compensation offered by flexible loads. In  [11, 31] , a version of the ETEM-SG is presented that considers the uncertainty of investment costs and of availability of technologies and transmission capacity lines. A static robust optimization approach is used to solve the problem. In  [32] , a robust multiperiod formulation of the ETEM, with uncertain demand response, is developed to better control the level of conservatism in planning. Finally, in  [33, 34] , two robust versions of the ETEM are linked to a mean field game model that presents the charging behavior of a large fleet of electric vehicles (EVs). This paper is an original application of the ETEM for the energy database of the GM region.
Methodology This research paper proposes a model for optimal expansion planning of the existing and future technologies in the energy sector of the GM region up to 2050, while meeting GHG emission reduction targets. To do so, we use the formulation of the Energy-Technology-Environment Model (ETEM). Introduced for the first time in  [28, 29] , the ETEM is an open-source energy model designed to analyze energy systems at an urban scale. For example, the ETEM has been applied to model the energy system of the Midi-Pyrénées region in France  [28]  and the Arc Lémanique region in Switzerland  [11]. We slightly modified the formulation of the ETEM to adapt it to the Montreal database. For example, contrary to the original version which calculates GHG emissions at the process level, we calculated emissions based on the total primary energy consumption in the entire system.
Figure2provides a summary of the important input and output of the ETEM model calibrated for the GM region. The input data includes energy demand, energy prices, resource availability, technical and economical information for technologies, and the carbon content of different fuels. Outputs correspond to the optimal capacity expansion plan, optimal imports and exports of the energy commodities, and the marginal costs of CO 2 emissions. Further details on the energy database of the GM region are provided in Appendix B.
Simple Summary: Currently, genomic databases offer a vast amount of information on mutational profiles and records of statistically significant genetic associations with diseases. However, the functional interpretation of frequently mutated genes implicated in cancer is essential for the development and clinical implementation of efficient targeted therapies. This review identifies and describes the most affected signaling pathways that are found deregulated in several cancer types and reports on corresponding targeted therapies, aiming to unravel literature gaps and to highlight targets of high therapeutic potential. To this purpose, we collected gene lists from the TCGA Pan-Cancer Atlas and OncoKB and employed the Onco Query Language (cBioPortal) search, to identify somatic driver events in 10,439 tumor samples.
Gene lists were created by collecting data on signaling pathways from the TCGA Pan-Cancer Atlas publications (3004 genes in total, available in https://www. cell. com/pbassets/consortium/pancanceratlas/pancani3/index. html (accessed on 1 November 2021)). Then, we filtered only those genes that belong to the OncoKB cancer gene list (340 genes), (version update: February 2021). Using the Onco Query Language (OQL) provided by cBioPortal, we searched specifically for somatic driver mutations in these genes in 10,439 mutationally profiled tumor samples (10,066 primary, 364 metastatic and 9 recurrent) included in 32 TCGA Pan-Cancer Atlas studies. We ascertained that more than 95% of the samples affected by driver events in the genes of interest (7915 out of 8276) belonged to the "primary origin" category, and therefore became the focus of subsequent analyses.
Data were extracted from the cBioPortal for Cancer Genomics open-access resource. Somatic driver mutations were identified in 204 of the 340 cancer genes in this particular dataset, so their corresponding pathways were marked for further analyses. The selection of the driver events was made in line with the definition of cBioPortal (https://www. cbioportal. org/oql#driver (accessed on 1 November 2021)) and OncoPrint (default: OncoKB and CancerHotspots). As such, mutations, fusions and copy number alterations constitute 'drivers'. Note that germline and somatic modifiers only apply to mutations and that very few studies on the public cBioPortal contain germline data. The types of alterations found in the 7915 samples are the following: frame_shift deletions or insertions, fusions, in frame deletions or insertions, missense mutations, nonsense mutations, nonstop mutations, slice regions or sites and translation start sites.
Data management, calculations and graph construction were performed using Spyder IDE, a scientific Python development environment. Numerous TCGA Pan-Cancer Atlas efforts have been made to elucidate the genomic background of cancer, each focusing on the deregulation of a different physiological cellular procedure  [14]. Each one of these procedures involves a number of signaling pathways that contain genes with a distinct tumorigenic potential (Figure  1 ). Furthermore, our mutational data analysis has shown that most cancers are characterized by deregulation of a group of pathways, rather than a single signaling pathway, but in a distinct pattern from other cancer types, while in some tumor types, a subtype-related differential representation of altered pathways or even a stage-dependent pathway perturbation also seems to exist (Figure  2 ).
The Python code, as well as the typed query for driver events in the genes of interest using the cBioPortal Onco Query Language (OQL) can be found in the supplementary information (Supplementary Materials S1 and S2). This review therefore focuses on the ten most frequently deregulated signaling pathways and as such only the results pertaining to these pathways are discussed below. In the next sections, we describe how specific genetic alterations/mutations in encoding genes of a given pathway may lead to carcinogenesis and/or cancer progression. For each pathway, a brief description is provided regarding its implication in cancer development, along with a description of the most highly mutated genes, and their percentile frequencies, as calculated in our analysis. In addition, we list some related targeted therapies that have been approved by the Food and Drug Administration (FDA) and are currently being integrated into clinical practice, as well as some emerging therapies which are currently being tested in clinical trials.
Such alterations shut down one of the cell cycle's checkpoints, as they force the p16 INK4a protein to lose its Cdk-binding ability, thereby being unable to prevent the G1/S transition  [45] [46] [47]. From the remaining two thirds of cases, an aberrant splicing involving the D153 residue appears in 5. 16% of all CDKN2A affected cancer patients. Changes in this position may inactivate both CDKN2A gene products, i. e. , p16 INK4a and p14 ARF , leading to loss of cell cycle control via both pRB and p53 inactivation  [46]. Factors upstream of p53 are also affected and, along with the ATM kinase, play a vital role in the activation of p53 in response to DNA damage  [48] [49] [50] [51] [52] [53] [54]. In our dataset, non-sense mutations leading to premature truncated forms of the ATM protein product represented more than one third of all ATM mutated cases, with R250* being the main representative.
In this context, eprenetapopt (APR-246), a mutant-p53 conformation resetting agent, is probably the most promising compound  [61]  and the only therapy of this category that is currently being tested in a phase III clinical trial (NCT03745716); on the other hand, a phase III trial of idasanutlin (NCT02545283), another emerging MDM2 inhibitor, was recently terminated due to low efficacy. The results of such clinical trials, as well as the efforts to improve the properties of the relevant compounds are highly anticipated. Apart from p53, there are four FDA approved anticancer drugs targeting CDKN2A signaling: abemaciclib, palbociclib, ribociclib and trilaciclib  [62] [63] [64] [65]. All these therapeutic agents act as CDK4/6 inhibitors, aiming to restore the inactivated CDKN2A  [66, 67]. However, it has been noted that p16 INK4a loss does not necessarily predict response to CDK4/6 inhibitors  [68] [69] [70] [71] [72].
Both mechanisms lead to increased levels of the activated GTP-bound form of the KRAS protein, resulting in uncontrolled mitogenic processes via a constitutively active signal transduction  [80, 83]. V600 is the most prevalent mutated codon of the BRAF gene, occurring in 81. 74% of all BRAF mutated primary tumors in our dataset, while rearrangement of BRAF with a variety of genes seemed to occur in only 4. 36% of these samples. In the majority of cases where a V600 variant exists, the valine residue is substituted by glutamic acid (V600E), enhancing the serine/threonine kinase activity of BRAF, thus leading to the abrogation of extracellular signals, promoting cell growth and proliferation  [84] [85] [86]. In contrast to BRAF, there is no hotspot position for the NF1 gene. The most common somatic mutation of NF1, namely R2450*, barely exceeds 3% of all identified variants in our cohort.
For many years the KRAS gene was considered untargetable  [92] [93] [94] [95]. A milestone study in 2021, leading to the discovery of the first KRAS-targeted therapy using sotorasib, an eclectic KRAS G12C inhibitor, was approved for adult NSCLC patients carrying this variant who had previously been treated with at least one systemic therapy  [96]. Another selective KRAS G12C inhibitor, adagrasib, owing to its tolerability and clinical effectiveness, was granted a Breakthrough Therapy Designation by the FDA and its approval is expected soon  [97]. With several more clinical trials underway e. g. , JDQ-443/NCT04699188, mesenchymal stromal cells-derived exosomes with KRAS G12D siRNA/NCT03608631 and anti-KRAS G12V mTCR PBL/NCT03190941), a new era seems to be emerging for cancer treatment. Furthermore, over the last ten years, three selective BRAF V600E inhibitors have been approved by the FDA: vemurafenib, dabrafenib and encorafenib  [98] [99] [100].
Lipid Metabolism Both lipid synthesis and catabolism are essential for the maintenance of membrane functionality, protein trafficking, immune cell responses, signaling, as well as coverage of metabolic demands, such as energy production and storage  [101] [102] [103] [104] [105]. It has been shown that cancer cells manage to retain a high proliferative potential, through various metabolic modifications  [13, 106, 107]. According to our analysis, more than 40% of patients of one in three cancer types/subtypes are characterized by driver mutations in genes involved in lipid metabolism. In uterine endometrioid carcinoma, astrocytoma, oligodendroglioma and oligoastrocytoma this proportion reached or exceeded 80%, while, as with the two pathways discussed above, no primary uveal melanoma tumor of our dataset was affected (Figure  3 ).
Currently, there are eleven clinically available therapies that target the signaling of four out of the 24 lipid metabolism-related genes found mutated in our dataset (Table  2 )  [91]. As our analysis suggests, when lipid metabolism is deregulated on account of a genetic change, this alteration invariably affects one of its aforementioned PI3K/AKT signaling-mediating regulators. Hence, inhibition of the PI3K/AKT signaling axis is suggested to be the main goal of personalized medicine for the treatment of tumors bearing such alterations. When PI3K catalytic subunit inhibitors, both isoform-specific, such as alpelisib, and pan-isoform, such as copanlisib and duvelisib, as well as selective MTOR inhibitors, including everolimus and temsirolimus, are employed, they seem to offer a significant PFS-or even OS-benefit to patients with a variety of blood or solid malignancies  [132] [133] [134] [135] [136].
In addition, ivosidenib, an inhibitor of IDH1 R132 mutants, has been approved by the FDA, for the treatment of acute myeloid leukemia (AML) patients harboring these variants  [137] , while its effectiveness in other IDH1-deficient cancer types is currently being tested in several ongoing clinical trials (e. g. , advanced and metastatic cholangiocarcinoma/NCT02989857, chondrosarcoma/NCT04278781, cholangiocarcinoma-chondrosarcoma-glioma-other advanced solid tumors/NCT02073994, recurrent ependymoma-recurrent ewing sarcoma-recurrent hepatoblastoma/NCT04195555, etc. ).
The PI3K/AKT Pathway The impact of the PI3K/AKT signaling network on diverse cellular functions is well established. Many of these, including cell growth and proliferation, survival, motility, cellular metabolism, immune system functions and angiogenesis, are tightly intertwined with cancer development and progression and as a result a lot of research has been dedicated to unraveling the deregulation mechanisms of this pathway in cancer  [138] [139] [140] [141]. In 26 of the 36 cancer types of our dataset, more than 10% of patients carried at least one driver mutation in genes involved in this pathway. Uterine malignancies showed the highest mutational rates with 93. 3% of uterine endometrioid carcinoma patients being affected, while the corresponding proportion of the remaining uterine tumors analyzed exceeded 60%.
Overall, the PI3K/AKT signaling-promoting behavior of p85alpha mutants, places PIK3R1-targeting in the same therapeutic context as the other major effectors of this pathway, PIK3CA and PTEN. As shown in Table  2 , the available agents targeting the signaling of these genes are essentially the same. In addition to PI3K and MTOR inhibitors, significant efforts are being made to develop AKT inhibitors  [147, 148]. Most of the ongoing clinical trial test agents exert a pan-AKT (AKT1, AKT2 and AKT3) inhibition. Of those, capivasertib and ipatasertib have demonstrated the most encouraging results and are now tested in several phase III trials mainly regarding breast and prostate cancer patients  [149]  (NCT03997123/NCT04493853/NCT04862663/NCT04305496 and NCT03072238/NCT03337724/NCT04060862/NCT04650581/NCT04177108, respectively).
These mutations induce changes in the WD40 domain, altering the interaction potential of FBW7, probably via both hydrophobic and electrostatic interactions, as well as by limiting the contact surface because of the shorter substitute sidechains (mainly cysteine, histidine, glycine and glutamine)  [157]. Given that several FBW7 interactors act as regulators of cell growth, apoptosis and proliferation  [158] [159] [160] [161] [162] [163] ; prevention of their degradation may result in tumorigenesis. Even though the EP300 gene is usually altered by nonsense mutations, the most recurrent mutations fall into three other categories. The D1399N substitution is the most prevalent somatic mutation of this gene, accounting for 7. 29% of EP300-mutated primary tumors in our working dataset. Missense mutations in this position were shown to change the conformation of the p300 protein histone acetyltransferase (HAT) domain, leading to abolishment of its autoacetylation activity, which is essential for appropriate function  [164, 165].
These observations, in conjunction with the arisen extended transcriptional changes, dictate a tumor promoting effect for these mutations  [175, 178]. The functional impact of frameshift deletion I1084Sfs*15, which is found in 4. 52% of CREBBP-altered samples thus far remains obscure. Proteins involved in either the attachment or the removal of ubiquitin moieties are barely exploited in clinical practice nowadays  [179]. An exception to this rule is provided by thalidomide analogues lenalidomide and pomalidomide, which have been approved for the treatment of various blood malignancies and exhibit anti-tumor activities by altering the specificity of cereblon, which constitutes the substrate recognition component of the CRL4 E3 ubiquitin ligase complex  [180, 181]. Nonetheless, targeting of the proteolytic machinery is primarily oriented to proteasome inhibition, with three inhibitors-bortezomib, carfilzomib and ixazomib-already approved for the treatment of multiple myeloma and mantle cell lymphoma  [182] , while other agents, such as delanzomib (CEP-18770) and marizomib or salinosporamide A (NPI-0052)  [183]  are currently being tested in clinical trials as potential treatment options for solid tumors (NCT00572637 and NCT03345095, respectively).
Similarly, two other truncations, namely the R1114* and R876* mutants, also lose the axinand most b catenin-binding sites  [194, 195]. In all three cases, the subsequent b catenin accumulation and nuclear entry permits activation of the TCF/LEF1 transcriptional complex, thereby promoting cellular proliferation and tumorigenesis  [192]. Somatic mutations in the CTNNB1 (catenin-beta 1) gene, which is involved in the regulation of cell adhesion and gene transcription, are almost exclusively missense mutations. In particular, aa substitutions at six specific positions  (32, 33, 34, 37, 41 and 45)  represent more than 85% of all affected patients in our dataset. Among them, S33, S37 and D32 replacements were the most prevalent, affecting 18. 51%, 17. 44% and 16. 01% of all cases, respectively. The protein region between D32 and S45 participates in the phosphorylation of b catenin from CK1alpha and GSK3beta (components of its destruction complex), as well as in the interaction of phosphorylated b catenin with its E3 ligase substrate recognition component, FBW1  [196, 197].
Four such constructs have exhibited the most encouraging results and their efficacy is currently evaluated in phase II clinical trials of both solid and blood cancer patients. In this context, WNT974 (NCT02278133)-a porcupine inhibitor that impedes WNT secretion and activity, Foxy-5 (NCT03883802)-a WNT5a mimetic, PRI-724 (NCT01606579)-an antagonist of the b catenin coactivator CBP, and DKN-01 (NCT03395080)-a monoclonal antibody that neutralizes the activity of WNT/b catenin axis inhibitor DKK1, are now in the spotlight of WNT pathway targeting.
The most encouraging results come from the development of inhibitors against gamma-secretase-which is responsible for the final NICD-releasing NOTCH cleavage-and deltalike protein 3, a NOTCH ligand, with some of the relevant cancer-related clinical trials being in advanced stages. Specifically, the efficacy of gamma-secretase inhibitors (GSIs) nirogacestat/PF-03084014 (NCT03785964) and MK0752 (NCT00756717) is currently evaluated in phase III trials in adults with desmoid tumor and in early stage breast cancer patients in combination with tamoxifen respectively, while the tesirine conjugated antidelta-like protein 3 mAb rovalpituzumab (Rova-T) (NCT03061812) is being tested in a phase III clinical trial in small-cell lung cancer (SCLC) patients with disease progression following platinum-based chemotherapy and overexpressing delta-like protein 3.
24%, 22. 52% and 20. 04% of cases, respectively. At the same time, no such alterations were found in patients with renal clear cell carcinoma, acute myeloid leukemia, uveal melanoma or pheochromocytoma (Figure  3 ). Indisputably, the retinoblastoma tumor suppressor RB1 and the previously discussed CDKN2A are the most commonly mutated cell cycle genes, identified in 44. 43% and 41. 11% of all cell cycle-perturbed primary tumors, respectively; despite ranking third in mutational frequency, the CDKN1A gene was found mutated in 6. 76% of assessed tumors. Somatic mutations were highly dispersed along the RB1 gene, with 203 of the 928 aa-encoding codons found to be implicated in a driver event in our dataset. Even though more than 40% of these genomic changes were non-sense mutations, the most recurrent appears to be the splice site mutation X405_splice, which nevertheless accounts for only ~3% of RB1-mutated tumors.
Thus far, therapeutic targeting of the cell-cycle is largely based on CDK4/6 inhibition  [235]. Three such inhibitors, palbociclib, ribociclib and abemaciclib have already received FDA approval either as monotherapy or in combination with hormone therapies, for the treatment of advanced HR + /HER2 -breast cancer  [62] [63] [64]. Recently, another CDK4/6 inhibitor, trilaciclib, was also approved for the prevention of chemotherapy-induced myelo-suppression in small cell lung cancer (SCLC) patients  [65]. In parallel, many more such inhibitors are currently being tested in clinical trials for their potential to confer improved anti-tumor activity, but accompanied by less toxicity. Of these, dalpiciclib (SHR6390) is the only compound currently tested in phase III trials (NCT03966898 and NCT03927456), while many pan-CDK inhibitors are being evaluated in earlier phases of clinical development  [91].